1. Field of the Invention
The present invention relates to a (co)polymer suitable for bases or auxiliary agents for external application (for example, hydrophilic gels, tackifiers, thickeners or excipients) to be coated or plastered onto the skin or mucosa of a human being or animal, such as ointment agents (ointment, hydrogel, jelly or cream), plastering agents (molded poultice, tape agent or plaster agent), sticky (or adhesive) bandages (sticky bandage, strap, wound strap, surgical tape, taping material, supporter), and to preparations for external application containing same.
2. Description of the Related Art
The various pharmacologically active ingredients currently used for the therapy or prophylaxis of diseases of human beings or animals, or for maintaining health and body energy, include many which require administration or application 3 to 4 times per day, because of a short persistency of the action thereof. These ingredients, although having excellent therapeutical effects, are known to frequently cause not only the problems of a cumbersome administration or a non-compliance on the patient's side, and a laborous and time-consuming administration, but also side effects or drug problems due to an excessive administration of these pharmacologically active ingredients.
As the means for solving such problems, many attempts have been made in the prior art to formulate pharmacologically active ingredients in external applications such as ointments, poultices, and tape agents to thereby obtain a persistent therapeutical effect by an absorption through the skin.
Among the above, ointments are used for the therapy of local diseases such as inflammation or various skin diseases, or for systemic diseases such as angina pectoris, and are frequently used as a method of obtaining therapeutical effects at the afflicted sites while avoiding the systemic side-effects caused by oral agents.
In the prior art, as the base of these ointments, there are used oily bases such as vegetable oils, lard, and glycerine, and water-soluble bases such as macrogols, but the former cause problems such as a stickiness on the skin, oily feeling at the coated surface, a bad odor, or a restriction of the formulation of water-soluble pharmacologically active ingredients, and the latter cause problems such as a poor absorbability of the pharmacologically active ingredients, and do not provide the required therapeutical effect.
To solve these problems, hydrogel bases containing water-soluble polymers such as polyacrylic acid, starch, gum tragacanth, alginic acid, and cellulose derivatives formulated therein are employed. Particularly, hydrous gel bases containing water and polyacrylic acid, alcohols, amines formulated therein have an excellent absorbability of pharmacologically active ingredients, and are used for the amelioration of the therapeutical effects of antiinflammatory agents such as indomethacin and ketoprofen, and adrenocortical hormones such as fluocinolone acetanide (e.g., Chem. Pharm. Bull., 29, 2338 (1981) and Japanese Unexamined Patent Publication (Kokai) No. 58-83621).
Nevertheless, since the salts of polyacrylic acid are anionic polymers, they cause problems such as the forming of complexes with basic pharmacologically active ingredients, to thereby lower the absorbability of the pharmacologically active ingredients to the skin, and further, have a poor solubility of water-insoluble pharmacologically active ingredients into the base, to thereby have a lower absorbability, because they are dispersed or suspended in the liquid phase. Many pharmacologically active ingredients assume the forms of salts, but when salts are added, the thickening property of polyacrylic acid is markedly lowered, and therefore, it is extremely difficult in practical application to formulate a pharmacologically active ingredient which takes the form of a salt (e.g., Japanese Unexamined Patent Publication (Kokai) No. 62-123112). Further, alkali metal sheets of polycarboxylic acids have a poor affinity for alcohols such as ethanol and propylene glycol, and when alcohols are to be formulated, they must be neutralized with organic amines such as diisopropanolamine, and a skilled technique is required for making the rheological characteristics of the gel uniform, whereby the steps are necessarily complicated (e.g., Japanese Unexamined Patent Publication (Kokai) No. 61-275216).
On the other hand, the plaster agent can be administered in accurate doses, and at the same time has a occlusing effect due to a backing material, and can formulate a pharmacologically active ingredient at a high concentration within a thin adhesive layer about 10 .mu.m thick, and therefore, has an excellent absorbability of a pharmacologically active ingredient and is used for the application of a therapeutical drug agent for systemic heart diseases, such as nitroglycerine and isosorbide dinitrate. Also, in the field of surgery, various sticky bandages have been employed for fixing materials to be adhered, such as gauze and plaster cast, trauma preventers such as supporters and taping, and for the protection of the skin or the reinforcement of trauma sites.
Nevertheless, most of these plaster agents for therapy or for sticky bandages for surgery employ water-insoluble polymers such as alkyl acrylate type copolymers, styrene-isoprene copolymers, silicon type copolymers, and have serious problems in that steaming or an irritation of skin occurs because of the occulusing action thereof the skin, physical keratic peel-off due to a strong adhesion, or an allergy caused by the base ingredient (e.g., Phamacia, 7 (1), 24 (1971), Br. J. Dermatol., 112, 461 (1985), J. Invest. Dermatol., 71, 378 (1978)).
As the means of alleviating the skin 10 irritation caused by a plaster agent for therapy or a sticky bandage, to the knowledge of the present inventors, the following methods have been proposed:
1) the method of preventing a steaming eruption of the skin by enhancing the water vapor permeability of the backing material (e.g., Japanese Unexamined Patent Publications (Kokai) Nos. 54-70340, 61-210026); PA1 2) the method of preventing a steaming eruption of skin by making the adhesive layer porous and adding a water-soluble polymeric substance such as a cellulose derivative, to thereby enhance the water vapor permeability of the adhesive layer (e.g., Japanese Unexamined Patent Publications (Kokai) Nos. 49-97058, 59-232553); PA1 3) the method of using an adhesive having an enhanced hydrophilic property, such as acrylic copolymers having ether groups, (methacrylamide copolymers, mixtures of styrene-isoprene block copolymers and gelatin, polyoxyalkylene-modified organosiloxanes, butadiene copolymers containing --OH, --NCO groups, silicon type copolymers, etc. (e.g., Japanese Unexamined Patent Publications (Kokai) Nos. 57-85318, 59-42314, 61-187867, 62-155855, 62-263275, 63-46163, 63-66277, 1-85267, 1-99563); PA1 4) the method of lowering the adhering force by using as the adhesive a polymer composed of fine particles (e.g., Japanese Unexamined Patent Publication (Kokai) No. 61-234865); PA1 5) the method of lowering mechanical stimulation during the stretch-shrink effect by enhancing the stretch-shrink property of the backing material (e.g., Japanese Unexamined Patent Publication (Kokai) No. 60-75062); PA1 6) the method of extracting low molecular weight components in the adhesive layer with an alcohol (e.g., Japanese Unexamined Patent Publication (Kokai) No. 52-75062); PA1 7) the method of alleviating skin irritation by formulating extracts from vegetables such as Shikon, Obaku, Nanten and Kanzo, vegetable extract components such as glycyrrhizic acid, and antihistamines such as diphenhydramine (e.g., Japanese Unexamined Patent Publications (Kokai) Nos. 56-156153, 60-69016). PA1 (1) an equilibrium is established between the water evaporated from skin and external water vapor, to prevent a steaming eruption of the skin; PA1 (2) since the adhesion force is weaker than that of the alkyl acrylate type or the rubber type adhesive, a mechanical peel-off of skin keratin can be prevented; PA1 (3) since the adhesion force is stronger than the poultice of the prior art using sodium polyacrylate as the adhesive, the base thickness can be made thinner; PA1 (4) since a solvent mixture of water and alcohols is used, a wide range of pharmacologically active ingredients, including both water-soluble and lipied-soluble ingredients, can be formulated at high concentrations; PA1 (5) because there are few anionic groups in the copolymer, substantially no complex formation with basic pharmacologically active ingredients occurs as in sodium polyacrylate; PA1 (6) alcohols enhance the migratability of the pharmacologically active ingredients to the skin; PA1 (7) water swells the skin corneum to lower the diffusion resistance of the skin to the pharmacologically active ingredients,
Even when these methods are employed, however, it is difficult to sufficiently lower the skin irritation. Further, in the plaster agent for therapy, which has been deemed to have a high absorbability of pharmacologically active ingredients, it is difficult to dissolve a water-soluble pharmacologically active ingredient in the form of a salt to a high concentration, and thus it has been difficult to effect a percutaneous absorption to the extent of obtaining a therapeutical effect on systemic diseases, except for specific pharmacologically active ingredients.
On the other hand, the bases for poultices used in the prior art for a therapy of arthritis and muscle pain are known to have a much lower skin irritation, compared with adhesives of the alkyl acrylate type, the rubber type or the silicon type. This is considered to be because the adhering force of the poultice is very weak, compared with tape agent, whereby the mechanical peel-off of skin keratin does not occur, and further, an equilibrium is established between the water vaporized from skin and the water vapor in the external atmosphere, whereby steaming eruptions can be prevented (e.g., J. Pharm. Pharmacol., 41,152 (1989)).
From such standpoints, there has been proposed a method of formulating a water-soluble polymer such as alkali metal salts of polyacrylic acid and water in alkyl acrylate type tackifiers, and a method of using a hydrous gel base containing a moisturizer such as glycerine and water as the components (e.g., Japanese Unexamined Patent Publications Nos. 60-123416, 60-99180, 61-257919, 63-238017).
In the former method, however, in the experience of the present inventors, when an alkali metal salt of polyacrylic acid is formulated in an amount which enables it to function as a hydrous base, a marked lowering in the adhesive force occurs, and thus the adhesion during plastering is often poor. In addition, since a water-soluble polymer is formulated into a non-water-soluble adhesive inherently having no compatibility, a phase separation occurs during the coating of the adhesive layer, and thus problems arise such that the moldability and working efficiency are worsened.
In poultices using an alkali metal salt of polycarboxylic acid, as represented by sodium polyacrylate of the prior art, as the thickener, because these thickeners are anionic polymers, problems arise in that they form complexes with basic pharmacologically active ingredients, as in the case of the hydrogel ointments as described above, to lower the absorbability, and that the adhering property is remarkably lowered by an addition of a salt. Further, most of these thickeners have a poor affinity for alcohols such as ethanol and propylene glycol, and thus it is difficult to formulate water-insoluble pharmacologically active ingredients to a high concentration.
Further, to obtain a sufficient adhesion to the skin, a base thickness of about 1 mm or more is generally required, thereby ensuing that not only a feeling of foreign matter or prevention to movement of the movable portion, or a defective adhesion to a movable site such as finger tip or joint may occur, but due to a difficulty in formulating pharmacologically active ingredients to high concentration, it has been also impossible to cause pharmacologically active ingredients to be absorbed to an extent such that the required effect for systemic diseases is obtained.
Thus, to the the knowledge of the present inventors, there has not been obtained a base for an external application for therapy or for surgery which satisfies all requirements for a formulatability, absorbability, adhesiveness, and less skin irritation of the pharmacologically active ingredient.
On the other hand, it is known in the art that alcohols such as ethanol, isopropanol, propylene glycol, and glycerine, can enhance the percutaneous absorbability by enhancing the solubility of the pharmacologically active ingredient to the skin, or the hydration of the skin (e.g., J. Pharm, Sci., 78, 402 (1989), Pharm Tech Japan, 12, 130 (1988)).
Also, ethanol and isopropanol have sterilizing and disinfecting actions, and if these can be formulated into the adhesive, the prevention of skin irritation by bacterial proliferation as well as the effects of a sterilization and disinfection of wounded portions can be expected. Further, in a hydrous base such as a hydrogel ointment or poultice, to prevent a proliferation of mold and bacteria, it is necessary to add a preservative such as propylparaben, but propylene glycol and benzyl alcohol have the preservative actions, and glycerine and 1,3-butylene glycol alleviate skin irritation due to ethanol (e.g., Konnichino Hifugaiyozai (see, for example, Skin External Application of Today), 47 (1981).
Nevertheless, problems arise with water-soluble polymers of the prior art when obtaining the external application base as intended by the present invention. More specifically, as mentioned above, alkali metal salts of polycarboxylic acid have a poor affinity for alcohols. As polymers soluble in water and alcohols, there are known polyvinyl pyrrolidone, hydroxypropyl cellulose, ethyl cellulose, and polyethylene glycol, but all of these have lower molecular weights than polyacrylic acid, and when used as the plastering agent, it is difficult to enhance the cohesion of the tackifier layer to the extent that no glue remains on the skin. On the other hand, polyacrylamides have relatively higher molecular weights, but have problems with respect to the safety of the human body.
On the other hand, it is difficult to add a low boiling solvent to the plaster base because heating and drying steps are included in the manufacturing process, and further, if a large amount of a solvent is added, the cohesive force will be lowered, and thus it has been impossible to add alcohols.
Thus, to the knowledge of the present inventors, there has not been obtained a polymer which has a high affinity for alcohols and can exhibit the effect of the external application base intended by the present invention.